1. Field of the Invention
This invention relates to the stabilization of a pharmaceutical composition containing acid salts of thieno-pyridine derivatives. The stabilization is achieved using a pharmaceutically acceptable, non-volatile organic acid, particularly citric acid.
2. Prior Art
Because of the need to facilitate manufacture, application or consumption of the drug, control of the unit dose, and ease of packaging and handling, drugs are commonly manufactured and marketed in combination with other ingredients of little or no therapeutic value. Against these considerations must be reflected the need to maintain the stability of the composition over the shelf life of the formulation in order to maintain the unit dose and to avoid any untoward effects which may arise from degradation of the drug or excipients.
Initially prepared pills and capsules of compositions containing a thieno-pyridine derived drug named ticlopidine hydrochloride (see U.S. Pat. No. 4,051,141) discolored during normal storage. Analysis of these materials showed degradation of ticlopidine was responsible for the discoloration. The presence of certain excipients such as gelatin, Povidone and magnesium stearate was determined to be the initiating factor in this degradation. In order to market an efficacious and acceptable drug of this structure in the proposed formulation, a means was needed for preventing this degradation which would not interfere with the action of the drug nor have a detrimental or deleterious effect on the user.
No information in the literature deals directly with the prevention of degradation in compositions of thieno-pyridine compounds insofar as is known. Anti-oxidant and chelating additives are available in the chemical arts. However, the selection, where drug formulations are concerned, is limited by the requirement that these additives be pharmaceutically acceptable at levels needed to stabilize compounds in formulations.
One class of anti-oxidant and chelating agent additives for stabilizing organic compounds and compositions is non-volatile organic acids. For example ascorbic acid and citric acid as well as malic acid and tartaric acid have all been used as stabilizers. Citric acid in particular has been used to stabilize fats and oils (U.S. Pat. Nos. 2,197,269 and 3,294,825), hydroquinone solutions (U.S. Pat. No. 3,855,150), and drugs such as fluocinolone acetonide (Great Britain Pat. No. 41034/62), PGE series compounds (German Pat. No. 2,353,797) and L-Dopa formulations (J7 9014-167). None of these references suggest, however, that citric acid or others of that additive class would be useful in stabilizing acid addition salts of thieno-pyridine compounds in solid dosage formulations, such as capsules and tablets.